A Journey of Dietary Therapies for Epilepsy in Iran: Diet Restriction in the Ancient Era to the Ketogenic Diet in the Modern Period

Epilepsy, in children, is a common neurological problem for referral to child neurology clinics. The prevalence of nonfebrile seizure in children (under 10 years old), is estimated from 5.2 to 8.1 per 1000. Also, the prevalence of epilepsy in Iran estimated about 5 %; it means 4 million people of Iranian population live with epilepsy in Iran. Although antiseizure drugs (ASDs) are the essential treatment modalities in most children, more than 30% of epileptic children have intractable seizures or they suffer from drug adverse effects secondary to these medications. Because only a limited number of epileptic patients benefit from surgical therapy using the additional therapeutic options is inevitable. There are many available nonpharmacologic proven therapies for refractory seizures that Dietary therapy ( Ketogenic Diet) is one of the important therapeutic options in this group. In this review, we will discuss the different features of pediatric epilepsy dietary therapies (Especially the Ketogenic Diet) in Iran and also the history of epilepsy in ancient Iran, utilization, effectiveness, side effects, tolerability, and acceptability as well as ongoing and future programs.


Introduction
Epilepsy, a global health problem, is a brain cortex disorder characterized by an enduring predisposition to generate epileptic seizures in any age, sex and geographical regions without racism or socioeconomically class discrimination. It is also associated with a personal, familial, economical and psychosocial burden (1,2). Up to 10% of the people worldwide experience at least one epileptic seizure Although antiseizure drugs (ASDs) are the essential treatment modalities in most children, more than 30% of epileptic children have intractable seizures or they suffer from drug adverse effects secondary to these medications.
Because only a limited number of epileptic patients benefit from surgical therapy using the additional therapeutic options is inevitable.
There are many available nonpharmacologic proven therapies for refractory seizures that Dietary therapy ( Ketogenic Diet) is one of the important therapeutic options in this group.
In this review, we will discuss the different features of pediatric epilepsy dietary therapies (Especially the Ketogenic Diet) in Iran and also the history of epilepsy in ancient Iran, utilization, effectiveness, side effects, tolerability, and acceptability as well as ongoing and future programs.
In a meta-analysis and systematic review study, the prevalence of epilepsy in Iran estimated nearly 5 %.It means that 4 million epileptic people live in Iran, considering a total 80 million of population .The authors notified that the result is much higher than reported prevalence in other countries (8).
Although antiseizure drugs (ASDs) have proven efficacy in treatment of epilepsy, unfortunately they are not always effective. Approximately 30-33% of patients have drug resistant epilepsy (DRE) even when they are treated with multiple ASDs (9,10). Current International League Against Epilepsy (ILAE) defines Drug-resistant epilepsy (also named intractable epilepsy or refractory epilepsy) as "failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drugs schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom" (10,11). DRE is a challenging aspect of children epilepsy treatment despite development of new generation of ASDs. Thus, a need for additional therapeutic options is inevitable (12,13). There are many available nonpharmacologic proven therapies for DRE. Dietary treatments are one of these therapeutic options (14).
In this review, we will address the different features of pediatric epilepsy dietary therapies in Iran including history of epilepsy in ancient Iran, utilization, effectiveness, side effects, tolerability, and acceptability as well as ongoing and future programs.

Historical Perspectives
The history of epilepsy

A) Epilepsy in the ancient world
The history of epilepsy is as old as the history of humanity in the world (15).The stone tablets of the Sakikku (meaning "all diseases"), a Babylonian text compiled around 1000 BC, is the first known detailed description of various seizure types.
The Sakikku refers to the epilepsy with the terms 'antasubba' and 'miqtu'. The translated Babylonian text describes epilepsy features in the words such as unilateral and bilateral fits, the epileptic cry, the defecation incontinence, simple and complex epileptic seizures, the epileptic aura and narcolepsy (16).The Babylonians believed that epilepsy is secondary to supernatural powers and patients with epilepsy considered as a "person possessed by a particular demon or evil spirit" (17).
The "falling sickness" is a translation of Sumerian term referring to descriptions of seizures (18).
There is additional ancient reports about epilepsy descriptions including:

1-Avestan or Zoroastrian Medicine
The Avesta, a collection of Zoroastrian holy writings, is the first Persian text that includes some documents of ancient Iranian medicine addressing the health and sickness. It was probably compiled during the 6th Century B.C., but the precise date is not determined. Apart from this Avestic reference, no other sources addressed to the Persian attitudes about epilepsy in those times (24, 25).

3-Medieval Islamic Period
In this period, epilepsy was one of important disease in the field of traditional Iranian neuroscience. 1-The patients with epilepsy must avoid not only excessive eating but also some foods such as cow and sheep meat, fish, onion, garlic, celery, cauliflower, and carrot.
2-The patients may need surgery. The "operating therapeutic model" is being followed for centuries, not only in Iran but also throughout the world.

3-Infants and young children with epilepsy should
be protected from excessively shrill noises. 4-Epileptic children should not be exposed to intensely bright lights.

5-
The patients with epilepsy must avoid hot and cold environments.
6-Extensive physical activity should be avoided either before or immediately after meals in epileptic patients.
7-It is better that meals be arranged so that one eats three times a day. He proposed that goat meat is much drier and thus reducing the process of "humidification" in the body.

8-The patients should eat goat meat instead
9-Celery eating, also, should be avoided because it excites the epilepsy, whereas coriander is beneficial because it inhibits the formation of vapors in the brain.
10-He recommends abstinence from "fresh fruit due to its high water content; the heavier vegetables such as cabbage, turnips, and radishes; and any food that produces evaporations that could pass into the brain" (39-43).

B) Modern period
In Iran, the first epilepsy diet therapy center as a  (4) the low glycemic index treatment (LGIT) (14).

KD studies in Iran
In parallel with increasing use of the KD in the other countries, physicians in Iran have started to treat patients with the KD and subsequently several studies performed about "the role of KD in treatment of epilepsy" during past 30 years. We categorized these studies into four groups and evaluated them based on some results predominantly effectiveness, patients' acceptance and side effects.

1) Classic KD studies
Publications on classic ketogenic diet in either  The results were as the following at the end of twelfth month for 123 patients: (1) Being seizure-free in 21 (9.8%) (2) More than 50% reduction in seizure frequency in 17 (17.7%) (3) Less than 50% reduction in seizure frequency in 21 (9.7%) (4) No response to treatment in 64 (31%) There was no statistically significant relationship between "response to treatment" and "follow up time", but there was significant difference between "response to treatment" and "reduced number of ASDs"48) ). Comparison of the studied parameters before the initiation of the diet and 3 months later showed significantly reduction in weight as well as serum levels of hemoglobin, calcium, glucose. Moreover, mean height growth velocity of 2.5cm per year was lower than normal growth velocity chart for age.
In conclusion, the results showed that although the patients' height growth velocity did not statistically change, their mean weight, and mean serum levels of hemoglobin, calcium, and glucose decreased significantly. The study, also, showed significant increase in the serum levels of Chol, TG, VLDL, and LDL/HDL and Chol/HDL (53).

2) Modified Atkins Diet (MAD) studies
A total of 3 published papers identified regarding modified Atkins diet by systematically searching in online databases (Table 2) 2) A control group (32 patients): a group that treated only with ASDs.
The primary outcome was at least 50% reduction in seizure frequency after 2 months of therapy. Also, the study showed that MAD co-therapy in case group can decrease seizure frequency 2.19 times in comparison with control group. No significant difference was shown between groups regarding baseline characteristic (58).

3) Low Glycemic Index Treatment (LGIT) studies
In searching of online databases, only one Treatment efficacy is not related to the levels of ketone yet correlates with lower and steadier blood glucose levels. In this study, LGIT had fewer side effects when compared to KD, a characteristic that is of great value for young children. The study showed 12.6% increase in serum triglycerides levels without significant metabolic implication.
Although elevated BUN levels detected in approximately one-third of patients that were probably the result of protein intake, there is likely no relationship between excessive protein intake and kidney failure in normal subjects. Therefore, it is recommended that LGIT patients followed closely up for renal function, higher fluid intake, and modifications in protein intake if necessary. In conclusion, this study indicated some benefits for LGIT as following: (1) High compliance and better tolerability compared with classic KD (2) LGIT is a safe and effective adjuvant antiepileptic therapy and may be used as an alternative to the classic KD in conditions when this diet cannot be used for any reason In another study, 40 children with DRE were treated with the classic KD and IVIG in 1995. The subjects categorized into two groups. The first group treated with classic KD and the second group treated with IVIG. Seizure frequency reduced 64% and 52% in the first and second group at the end of sixth month, respectively. However, difference between two groups was not significant (61). Epidemiologic studies conducted regarding to the prevalence of epilepsy are more than those of incidence in developing countries. Moreover, it is generally reported that epilepsy is more prevalent in developing than in developed countries (62,63).
During the last several decades of the 20th century, plenty of studies have been done to determine the prevalence of epilepsy in developing countries and children (64,65). The prevalence of epilepsy in developed countries ranges from 4 to 10 cases per 1000 (66).However, higher prevalence of epilepsy, ranging from 14 to 57 cases per 1000, have been reported in the developing and tropical countries. Higher prevalence of epilepsy in the these countries is probably due in part to differences in study methodology, problems with case ascertainment, lack of standardized classification, and poor were an essential epidemiologic data (71).

2) How many national epidemiologic studies have been done for epilepsy in Iran?
In searching of online databases, there were a few published articles regarding national epidemiology of epilepsy in Iran. In a study with population size of 35014, estimated crude prevalence (per 100 persons) was 12 (72).In another epidemiologic study, the prevalence of epilepsy was 1.8% and it was more common in females, unemployed people and higher educational level. Authors concluded that the lifetime prevalence of epilepsy in Iran is not low (73). In a meta-analysis and systematic review study, the prevalence of epilepsy in Iran estimated nearly 5%, a result that surprisingly was much higher than reported prevalence in other countries (8).

3) What is the prevalence of epilepsy in neighborhood and similar countries to Iran?
Asian studies documented a prevalence of 2.2 per 1000 persons in India (1,(74)(75)(76). The crude prevalence rate of epilepsy was 9.98 per 1000 persons in Pakistan and 7.0 per 1000 persons in Turkey. In both countries the prevalence was roughly twice as high in rural compared to urban areas (12,77).
Lifetime prevalence of 7.0 per 1000 persons has been reported in China (78). An approximate 724,500 people with epilepsy live in the Arab world. An incidence of 174 per 100,000 persons in 2001 was reported in a hospital-based study from Qatar. Prevalence ranged between 0.9/1,000 in Sudan and 6.5/1,000 in Saudi Arabia, with a median of 2.3/1,000. All the studies report higher prevalence in males, which was statistically significant in the Saudi study (79).
The incidence of epilepsy in children ranges from 41-incidence is consistently reported to be highest in the first year of life and declines to adult levels by the end of the first decade. The prevalence of epilepsy in children is consistently 187/100,000. Higher incidence is reported from underdeveloped countries. The incidence is higher than and ranges from 3.2-5.5/1,000 in developed countries and 3.6-44/1,000 in underdeveloped countries. Either prevalence or incidence seems highest in rural areas (79 -81).

3) What is the conclusion?
In almost all the Middle East countries, mental health units in ministries of health are also planning and implementing for epilepsy. In the Islamic Republic of Iran, the health information system, which includes mental disorders, also encompasses epilepsy (32).Therefore, in order to Iranian studies (14).In almost all studies, a conclusion have been similar: approximately 50-60% of children will have at least more than 50% seizure reduction, with one third have more than 90% response (85)(86)(87).
Several studies with retrospective, prospective and Meta analyses methodologies have indicated the efficacy of KD in intractable childhood epilepsies (88 -92). In a Cochrane review based Meta analyses of four randomized controlled studies (93)(94)(95)(96), the efficacy of KD on epilepsy was confirmed in 289 children and adolescents (97). A meta-analysis of 19 studies including a total of 1084 children showed more than 90% seizure reduction in one-third of patients and more than 50% seizure reduction in half of the patients (92).A large prospective KD study including 150 children with DRE, represented 50-90% seizure reduction in 26% of children and 90% seizure reduction in 31% of children (98).
A Chinese KD study including 317 children with DRE, showed more than 50% seizure reduction in 35%, 26.2%, and 18.6% of children after 3, 6 and 12 months, respectively (99). A recent meta-analysis of studies from 1925 to 1998 reports that 30% of patients have a 50% to 90% reduction in seizures and an additional 37% of patients have more than a 90% reduction in seizures (100).
In an Indian prospective study of 27 children with DRE, more than 50% seizure reduction occurred in 48% of patients at 6 months and, more than 50% seizure reduction occurred in 37% of patients at 12 months (101). KD is shown to be more effective than most ASDs and to reduce seizure frequency at least by 50% in half of the patients (102).Also, it is shown that recurrence rate of seizures is reduced after discontinuation of KD (103). It seems that efficacy with the KD does not decrease over the years, and seizure control continues many years later, surprisingly even after the KD has been discontinued (104,105).
The first formal, prospective, open-label study of MAD was designed and 20 children with DRE were treated (106).Also, the benefits of the MAD confirmed in two studies from Korea (107,108).
In a randomized controlled study of the MAD for the treatment of childhood epilepsy, the likehood of more than 50% and 90% seizure reduction was higher compared to the control group of standard medical management (109). In a study from Korea,